Since hydrocortisone was found to possess anti-inflammatory activity in treating rheumatoid arthritis, numerous synthetic analogues of glucocorticoids have been used to treat inflammatory and/or immune malfunctional diseases.
Although the beneficial effects of natural semisynthetic glucocorticoids have been appreciated for over 40 years, the limiting factor in the use of corticosteroids for the chronic and/or high dose treatment have been their systemic side-effects. Continual research to eliminate these systemic side effects was carried out and one of the side-effects, salt-retaining activity, was successfully abrogated by the introduction of C-1,2 double bond and C-16 methyl or hydroxyl substitutions shown by prednisolone, dexamethasone, betamethasone and triamcinolone. However, little success has been achieved in separating the anti-inflammatory effect of steroids from their adverse side-effects mainly occurred by glucocorticoidal activity.
Therapeutic approaches such as dosage forms for local application, alternate day administration and concomitant protective therapy have been employed to reduce the adverse systemic effects of potent steroids. Although systemic effects are known to be reduced when conventional steroids are applied topically, the use of steroids in large quantities for prolonged periods results in toxic systemic side-effects and all clinically effective topical steroids have the potential to produce adverse effects. Among the patients using steroids, children are particularly prone to the systemic effects of local steroid application and suppression of pituitary-adrenal function including growth retardation has been reported.
One structural modification by Laurent et al. in U.S. Pat. No. 3,944,577 was introducing a 20-carboxyl ester group. These compounds showed reduced systemic effects, however, the anti-inflammatory potency was not sufficient.
Steroid derivatives as described in U.S. Pat. No. 4,762,919 to Lee employed a similar strategy of introducing a carboxylic ester group to the steroid molecule. Several of these compounds showed high anti-inflammatory activity with greatly reduced systemic side-effects, but the synthetic procedures to the final compounds were found to be difficult. Therefore, other improvements were needed to provide acceptance for the new compounds.
It is an object of this invention to provide novel pregnane derivatives having carboxyester and amide groups connected to the cyclic acetal side-chain at strategic 17,21-17,20- or 16,17- positions of steroid molecule as safer anti-inflammatory steroids. It is another object of this invention to provide more convenient procedures for the synthesis of such steroid derivatives. Other objects will appear in the more detailed description which follows.